The present invention relates to novel organic compounds and compositions which are xcex11 adrenoreceptor antagonists, a method for inhibiting xcex11 adrenoreceptors and a method for treating benign prostatic hyperplasia (BPH), bladder outlet obstruction (BOO), neurogenic bladder, and gynecological syndromes such as dysmenorrhea (benign prostatic hypertrophy).
Adrenergic neurons play a major role in the innervation of heart, blood vessel and smooth muscle tissue. Compounds capable of interacting with adrenoreceptor sites within adrenergic nerves can initiate physiological responses including vasoconstriction, vasodilation and increased or decreased heart rate (chronotropic), contractility (inotropic) and metabolic activity. Adrenergic compounds have been employed to affect these and other physiological responses, however, many adrenergic compounds do not possess significant selectivity to enable desirable interactions with adrenergic adrenoreceptor sites. That is, these adrenergic compounds do not demonstrate a high degree of specificity for differing adrenoreceptor types within adrenergic neurons in order to obtain a desired physiological response separate from other possible, and perhaps less desirable, responses of the system under treatment.
Benign prostatic hyperplasia (BPH) is a condition which develops in middle-aged and elderly males and refers to the benign overgrowth of the stromal and epithelial elements of the prostate associated with aging. Symptoms of BPH include increased frequency of urination, nocturia, a weak urine stream and hesitancy or delay in starting the urine flow. Chronic consequences of BPH can include hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection.
Typically, BPH begins at an age in the mid-fifties and is the most common cause of urinary tract problems of men of this age. BPH is apparently rare in men prior to age 40, but at age 60, approximately 50% of men have histological evidence of BPH. The prevalence of BPH continues to increase with age until, at age 80, approximately 80% of men have pathological evidence of BPH.
Although prostatic hyperplasia is a common finding in older men, the presence of urinary symptoms is the essential feature that distinguishes simple anatomic enlargement of the prostate from prostatism, which is the clinical syndrome whereby the patient experiences significant obstruction of urinary flow. It is not uncommon in older men to have a palpably enlarged prostate without showing the symptoms of prostatism. From the patient""s perspective, however, the incidence and progression of urinary symptoms are more important than the mere presence of an enlarged prostate.
The discovery of large numbers of alpha-adrenergic adrenoreceptors in the smooth muscle of the prostatic capsule and bladder neck led to the conclusion that there is both a static and a dynamic component to bladder outlet obstruction associated with BPH (M. Caine, et al., Brit. J. Urol., 47: 193-202 (1975)). The static component derives from progressive hyperplasia of the aging prostate and leads to urethral narrowing with symptoms of urinary obstruction. Superimposed on this essentially mechanical problem is the variable degree of smooth muscle contraction controlled by the sympatheic nervous system which is affected by factors such as stress, cold and sympathomimetic drugs. It is this dynamic component which explains the often rapid fluctuations in symptoms observed in patients with prostatism.
The currently most effective treatment for BPH is surgical transurethral resection of the prostate (TURP). Since it removes the obstructing tissue (C. Chapple, Br. Med. Journal 304: 1198-1199 (1992)), it is a treatment which is directed to the static and dynamic components of BPH. However, this surgical treatment is associated with rates of mortality (1%) and adverse events (incontinence (2-4%), infection (5-10%), and impotence (5-10%)). A non-invasive alternative treatment would therefore be highly desirable.
The incidental clinical observation that urinary incontinence developed in women during antihypertensive treatment with prazosin (T. Thien, K. P. Delacre, F. M. J. Debruyne, R. A. P. Koene, Br. Med. Journal, 622-623 (1978)) and the experimental work of Caine (op cit.) contributed to the recognition of the potential role of selective a, adrenoreceptor blockade in diseases of the lower urinary tract. Subsequent studies by several groups have documented the functional role of xcex11 adrenoreceptors relative to xcex12 adrenoreceptors in the stromal compartment of the prostate, thereby providing a putative molecular basis for the use of specific xcex11 adrenoreceptor blockers in the non-surgical management of BPH (C. R. Chapple, M. L. Aubry, S. James, M. Greengrass, G. Burnstock, R. T. Turner-Warwick, Br. J. Urol. 63: 487-496 (1989)). Clinical efficacy of xcex11 antagonists in BPH has been demonstrated with several non-selective xcex11 blockers, including terazosin (Hytrin(copyright)), prazosin, and doxazosin. Treatment periods as short as two to four weeks with xcex11 adrenoreceptor blockers have shown objective improvements in the mean and maximum urinary flow rates (14-96%) with subjective improvements in patients""symptom scores (R. A. Janknegt, C. R. Chapple, Eur. Urol. 24: 319-326 (1993)). Longer term studies with terazosin, indoramin, prazosin and doxazosin have similarly demonstrated significant improvements in urinary flow rates and subjective symptom scores (R. A. Janknegt, op. cit., H. Lepor, G. Knapp-Maloney, J. Urol. 145: 263A (1991), W. Chow, D. Hahn, D. Sandhu, Br. J. Urol. 65: 36-38 (1990) and C. R. Chapple, T. J. Christmas, E. J. G. Milroy, Urol. Int. 45: 47-55 (1990)). However, these agents possess similar dose-limiting side effects including hypotension, dizziness and muscle fatigue.
In recent years, it has become clear that BPH and bladder outlet obstruction (BOO) are clinically differentiable, and that the severity of clinical BPH is related to many factors in addition to BOO (Lepor, H., Alpha Blockade for the Treatment of Benign Prostatic Hyperplasia, Urol. Clin. N. Amer., 22: 375-386, 1995.). For example, BOO may be related to other urological symptoms such as detrusor instability (Rosier, P. F. W. M., J. J. M. C. H. de la Rosette, H. Wijkstra, Ph.E. V. Van Kerrebroeck and F. M. J. Debruyne, Is Detrusor Instability in Elderly Males Related to the Grade of Obstruction?, Neurourol. Urodynam., 14: 625-633, 1995). Additionally, the role of extraprostatic xcex11 adrenoreceptors has been postulated as important in the etiology of lower urinary tract symptoms, such that antagonism of these receptors in spinal cord, ganglia, nerve terminals, bladder and bladder neck or the external urethral sphincter could be important in pharmacotherapy of urological conditions such as BOO or neurogenic bladder (Andersson, K-E., Prostatic and Extraprostatic a adrenoceptors Contributions to the Lower Urinary Tract Symptoms in Benign Prostatic Hyperplasia, Scand. J. Urol. and Nephrol., 30: 105-111, 1996). The recognition that women possess paraurethral glands which have anatomical, histological and biochemical similarities to the male prostate (Gittes, R. F. and R. M. Nakamura, Female urethral syndrome: A female prostatitis?, Western J. Medicine, 164: 435-438, 1996) suggests a potential role for xcex11 adrenoreceptor antagonist pharmacotherapy for amelioration of some symptoms of female urethral syndromes. In addition, xcex1 adrenoreceptors are functionally important to smooth muscle contraction in the uterus (Miller, M. D. and J. M. Marshall, Uterine Response to Nerve Stimulation: Relation to Hormonal Status and Catecholamines, Am. J. Physiol., 209: 859-863, 1965) and the modulation of sympathetic responses to catecholamines is enhanced by elevations in the levels of estrogens (Miller and Marshall, Uterine Response to Nerve Stimulation: Relation to Hormonal Status and Catecholamines, Am. J. Physiol., 209: 859-863, 1965). Consistent with this observation are data showing increasing levels of xcex1 adrenoreceptor responses and receptor density following estrogen administration to animals (Hoffman, B. B., T. N. Lavin, R. J. Lefkowitz and R. R. Ruffolo, Jr., Alpha-Adrenergic Receptor Subtypes in Rabbit Uterus: Mediation of Myometrial Contraction and Regulation by Estrogens, J. Pharmacol. Exp. Ther., 219: 290-295, 1981, and Roberts, J. M., P. A. Insel and A. Goldfein, Regulation of Myometrial Adrenoreceptors and Adrenergic Response by Sex Steroids, Mol. Pharmacol., 20: 52-58, 1981). Thus, hormonal regulation of xcex11 adrenoreceptor sensitivity could play a role in enhanced uterine contractions in dysmenorrhea, a condition for which selective xcex11 adrenoreceptor antagonists could have therapeutic potential. Therefore, there exists a need for a xe2x80x9curoselectivexe2x80x9d xcex11 antagonist with reduced side effect liabilities.
In its principle embodiment, the present invention provides compounds of formula I 
or a pharmaceutically acceptable salt thereof, wherein
n is an integer of 2-4;
R1 and R2 are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkynyl, amino, aminoalkyl, carboxy, carboxyalkyl, halogen, hydroxy, hydroxyalkyl, and nitro; and
R3 is selected from 
wherein A and B are independently selected from alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halogen, hydroxyalkyl, nitro, and phenyl.
All patents, patent applications, and literature references cited in the specification are herein incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.
It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof.
In its principle embodiment, the present invention provides compounds of formula I 
or a pharmaceutically acceptable salt thereof, wherein
n is an integer of 2-4;
R1 and R2 are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkynyl, amino, aminoalkyl, carboxy, carboxyalkyl, halogen, hydroxy, hydroxyalkyl, and nitro; and
R3 is selected from the group consisting of 
wherein A and B are independently selected from alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halogen, hydroxyalkyl, nitro, and phenyl.
In a preferred embodiment, compounds of the present invention have formula 11 
or a pharmaceutically acceptable salt thereof wherein R1, R2, A, B, and n are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula III 
or a pharmaceutically acceptable salt thereof wherein R1, R2, A, B, and n are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula IV 
or a pharmaceutically acceptable salt thereof wherein R1, R2, A, B, and n are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula V 
or a pharmaceutically acceptable salt thereof wherein R1, R2, A, B, and n are as defined in formula 1.
In another preferred embodiment, compounds of the present invention have formula VI 
or a pharmaceutically acceptable salt thereof wherein R1, R2, A, B, and n are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula VII 
or a pharmaceutically acceptable salt thereof wherein R1, R2, A, B, and n are as defined in formula I.
In another preferred embodiment, the present invention relates to pharmaceutical compositions which comprise a therapeutically effective amount of a compound of formula I-VII in combination with a pharmaceutically effective carrier.
In another preferred embodiment, the present invention relates to a method of antagonizing alpha-1 adrenoreceptors in a host mammal, particularly humans, by administering a therapeutically effective amount of a composition comprising a compound of formula I-VII.
In another preferred embodiment, the present invention relates to a method of treating benign prostatic hyperplasia in a mammal, particularly humans, by administering to a mammal an effective amount of a compound of formula I-VII.
In another preferred embodiment, the present invention relates to a method of treating bladder outlet obstruction in a host mammal, in particular humans, in need of such treatment by administering a therapeutically effective amount of a compound of formula I-VII.
In another preferred embodiment, the invention relates to a method of treating neurogenic bladder in a host mammal, in particular humans, in need of such treatment by administering a therapeutically effective amount of a compound of formula I-VII.
In another preferred embodiment, the invention relates to a method of treating uterine smooth muscle contraction in a female host mammal, in particular humans, in need of such treatment by administering a therapeutically effective amount of a compound of formula I-VII.
Definition of Terms
As used throughout this specification and the appended claims, the following terms have the following meanings.
The term xe2x80x9calkenyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl.
The term xe2x80x9calkoxy,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen, as defined herein. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
The term xe2x80x9calkoxyalkyl,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
The term xe2x80x9calkoxycarbonyl,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
The term xe2x80x9calkyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.
The term xe2x80x9calkynyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
The term xe2x80x9camino,xe2x80x9d as used herein, refers to a xe2x80x94NZ1Z2 group wherein Z1 and Z2 are independently selected from hydrogen and alkyl.
The term xe2x80x9caminoalkyl,xe2x80x9d as used herein, refers to an amino group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of aminoalkyl include, but are not limited, aminomethyl, 2-(amino)ethyl, and dimethylaminomethyl.
The term xe2x80x9ccarbonyl,xe2x80x9d as used herein, refers to a xe2x80x94C(O)xe2x80x94 group.
The term xe2x80x9ccarboxy,xe2x80x9d as used herein, refers to a xe2x80x94CO2H group.
The term xe2x80x9ccarboxyalkyl,xe2x80x9d as used herein, refers to a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl, and 3-carboxypropyl.
The term xe2x80x9ccyano,xe2x80x9d as used herein, refers to a xe2x80x94CN group.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogen,xe2x80x9d as used herein, refers to xe2x80x94Cl, xe2x80x94Br, xe2x80x94I or xe2x80x94F.
The term xe2x80x9chydroxy,xe2x80x9d as used herein, refers to an xe2x80x94OH group.
The term xe2x80x9chydroxyalkyl,xe2x80x9d as used herein, refers to one or two hydroxy groups, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, and 3-hydroxypropyl.
The term xe2x80x9cnitro,xe2x80x9d as used herein, refers to a xe2x80x94NO2 group.
Preferred compounds of formula I include, but are not limited to:
(+) 3-[3-(1,2,4a,5-tetrahydropyrazino[2,1-c][1,4]benzoxazin-3(4H)-yl)propyl]pyrido[2xe2x80x2,3xe2x80x2:4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione;
(xe2x88x92) 3-[3-(1,2,4a,5-tetrahydropyrazino[2,1-c][1,4]benzoxazin-3(4H)-yl)propyl]pyrido[2xe2x80x2,3xe2x80x2:4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione;
(+) 3-[4-(1,2,4a,5-tetrahydropyrazino[2,1-c][1,4]benzoxazin-3(4H)-yl)butyl]pyrido[2xe2x80x2,3xe2x80x2:4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione;
(xe2x88x92) 3-[4-(1,2,4a,5-tetrahydropyrazino[2,1-c][1,4]benzoxazin-3(4H)-yl)butyl]pyrido[2xe2x80x2,3xe2x80x2:4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione;
(+) 3-[4-(1,2,4a,5-tetrahydropyrazino[2,1-c][1,4]benzoxazin-3(4H)-yl)butyl]pyrido[3xe2x80x2,2xe2x80x2:4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione;
(xe2x88x92) 3-[4-(1,2,4a,5-tetrahydropyrazino[2,1-c][1,4]benzoxazin-3(4H)-yl)butyl]pyrido[3xe2x80x2,2xe2x80x2:4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione;
(xe2x88x92) 3-[2-(10-methoxy-1,2,4a,5-tetrahydropyrazino[2,1-c][1,4]benzoxazin-3(4H)-yl)ethyl]pyrido[2xe2x80x2,3xe2x80x2:4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione;
(+) 3-[2-(10-methoxy-1,2,4a,5-tetrahydropyrazino[2,1-c][1,4]benzoxazin-3(4H)-yl)ethyl]-8-chloropyrazino[2xe2x80x2,3xe2x80x2:4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione;
(xe2x88x92) 3-[3-(10-methoxy-1,2,4a,5-tetrahydropyrazino[2,1 -c][1,4]benzoxazin-3(4H)-yl)propyl]pyrido[2xe2x80x2,3xe2x80x2:4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione;
(xe2x88x92) 3-[4-(10-methoxy-1,2,4a,5-tetrahydropyrazino[2,1-c][1,4]benzoxazin-3(4H)-yl)butyl]pyrido[2xe2x80x2,3xe2x80x2:4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione;
(xe2x88x92) 3-[4-(10-methoxy-1,2,4a,5-tetrahydropyrazino[2, 1-c][1,4]benzoxazin-3(4H)-yl)butyl]pyrido[3xe2x80x2,2xe2x80x2:4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione;
(xe2x88x92) 3-[4-(10-methoxy-1,2,4a,5-tetrahydropyrazino[2,1-c][1,4]benzoxazin-3(4H) -yl)butyl]-8-chloropyrazino[2xe2x80x2,3xe2x80x2:4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione;
(xe2x88x92) 3-[2-(10-methoxy-1,2,4a,5-tetrahydropyrazino[2, 1-c][1,4]benzoxazin-3(4H)-yl)ethyl]-8-chloropyrazino[2xe2x80x2,3xe2x80x2:4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione;
(+) 3-[4-(10-methoxy-1,2,4a,5-tetrahydropyrazino[2,1-c][1,4]benzoxazin-3(4H)-yl)butyl]pyrido[2xe2x80x2,3xe2x80x2:4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione;
(+) 3-[4-(10-methoxy-1,2,4a,5-tetrahydropyrazino[2,1-c][1,4]benzoxazin-3(4H)-yl)butyl]pyrido[3xe2x80x2,2xe2x80x2:4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione;
(+) 3-[2-(10-methoxy-1,2,4a,5-tetrahydropyrazino[2,1-c][1,4]benzoxazin-3(4H) -yl)ethyl]pyrido[2xe2x80x2,3xe2x80x2:4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione;
(+) 3-[3-(10-methoxy-1,2,4a,5-tetrahydropyrazino[2,1-c][1,4]benzoxazin-3(4H)-yl)propyl]pyrido[2xe2x80x2,3xe2x80x2:4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione and pharmaceutically acceptable salts thereof.
Abbreviations which have been used in the descriptions of the Schemes and the Examples that follow are: Ac for acetyl; cbzCl for benzyl chloroformate; DMF for N,N-dimethylformamide; LAH for lithium aluminum hydride; and THF for tetrahydrofuran.
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes and methods which illustrate a means by which the compounds of the invention can be prepared.
The compounds of this invention can be prepared by a variety of synthetic routes. Representative procedures are shown in Schemes 1-2. 
Benzoxazines of general formula (11), wherein R1, R2, A, B, and n are as defined in formula I and wherein W, X, Y, and Z are CH; or one of W, X, Y, or Z is N; or both W and Z are N; can be prepared as described in Scheme 1. 2-Nitrophenols of general formula (1), purchased or prepared using known methodology, can be treated with epichlorohydrin as described in (Gupta et al., Indian Journal of Chemistry 13, 462-467 (1975); and Petrov and Stephenson, Journal Of Pharmacology, 5, (1953) pp 359-369) to provide epoxides of general formula (2). Epoxides of general formula (2) can be treated with (S) or (R) xcex1-methylbenzylamine to provide alcohols of general formula (3). Alcohols of general formula (3) can be treated with acetic anhydride or benzyl chloroformate and then oxidized under Swern conditions to provide ketones of general formula (4). Ketones of general formula (4) can be treated with 30% HBr in acetic acid and then treated with 5% platinum on carbon under 4 atmospheres of hydrogen to provide benzoxazines of general formula (5). The diastereomers, (5), can be separated via standard flash chromatography. The separated diastereomers, (6), can be treated with 1,2-dibromoethane and then treated with palladium on carbon and ammonium formate to provide enantiomerically pure hexahydropyrazino-benzoxazines of general formula (7). Hexahydropyrazinobenzoxazines of general formula (7) can be treated with bromoalkylnitriles, (8), and then treated with lithium aluminum hydride and aluminum chloride to provide amines of general formula (9). Amines of general formula (9) can be treated with isocyanates of general formula (10) from Scheme 2, wherein R is alkyl such as methyl or ethyl, to provide benzoxazines of general formula (11). 
Isocyanates of general formula (10), wherein A and B are as defined in formula I and wherein W and Z are N can be prepared as described in Scheme 2. Pyrazines of general formula (12), prepared as described in (Muehlman, F. L. and Day, A. R., JACS 78 (1956) 242), can be treated with phosphorous oxychloride as described in (Chem. Abstr., 56 (1962) 871 1 h) to provide 3-chloro-2-cyanopyrazines of general formula (13). 3-Chloro-2-cyanopyrazines of general formula (13) can be oxidized with potassium persulfate to provide N-oxides of general formula (14). N-oxides of general formula (14) can be treated with ethyl thioglycolate to provide 7-aminothienopyrazines of general formula (15). 7-Aminothienopyrazines of general formula (15) can be treated with phosgene to provide isocyanates of general formula (10) wherein W and Z are both N.
Isocyanates of general formula (10), wherein A and B are as defined in formula I and wherein W, X, Y, and Z are CH; or one of W, X, Y, or Z is N; or both W and Z are N; can be prepared as described in Scheme 2. Aminothienopyridines of general formula (16) wherein W, X, Y, and Z are CH; or one of W, X, Y, or Z is N; may be prepared as described in (Beck, JOC 37 (1972) 3224; Norman, M. H. et. al., J.Med.Chem., (1996) 4692-4703; and Dunn, A. D. and Norrie, R., J.Het.Chem., 24 (1987) 85-89), and can be treated with phosgene to provide isocyanates of general formula (10).
Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the Examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used.